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Gender-related differences in pulmonary arterial hypertension targeted drugs administration
Accepted Manuscript Title: Gender-related Differences in Pulmonary Arterial Hypertension Targeted Drugs Administration Author: Alberto M. Marra Nicola Benjamin Christina Eichstaedt Andrea Salzano Michele Arcopinto Luna Gargani Michele D´eAlto Paola Argiento Lorenzo Falsetti Paolo Di Giosia Andrea M. Isidori Francesco Ferrara Eduardo Bossone Antonio Cittadini Ekkehard Grunig ¨ PII: DOI: Reference:
S1043-6618(16)30780-0 http://dx.doi.org/doi:10.1016/j.phrs.2016.10.018 YPHRS 3370
To appear in:
Pharmacological Research
Received date: Revised date: Accepted date:
10-8-2016 30-9-2016 18-10-2016
Please cite this article as: Marra Alberto M, Benjamin Nicola, Eichstaedt Christina, Salzano Andrea, Arcopinto Michele, Gargani Luna, D´eAlto Michele, Argiento Paola, Falsetti Lorenzo, Giosia Paolo Di, Isidori Andrea M, Ferrara Francesco, Bossone Eduardo, Cittadini Antonio, Grunig ¨ Ekkehard.Gender-related Differences in Pulmonary Arterial Hypertension Targeted Drugs Administration.Pharmacological Research http://dx.doi.org/10.1016/j.phrs.2016.10.018 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Gender-related Differences in Pulmonary Arterial Hypertension Targeted Drugs Administration
Alberto M. Marra1*, MD; Nicola Benjamin2*, MSc; Christina Eichstaedt2*, PhD; Andrea Salzano3, MD; Michele Arcopinto3, MD; Luna Gargani4, MD, PhD; Michele D´Alto5, MD; Paola Argiento5, MD, PhD; Lorenzo Falsetti6, MD; Paolo Di Giosia7, MD; Andrea M. Isidori8, MD, PhD; Francesco Ferrara9, MD,PhD; Eduardo Bossone9, MD, PhD; Antonio Cittadini3, MD; Ekkehard Grünig2, MD
1
IRCCS SDN, Via Gianturco 113, 80143 Naples, Italy Centre for Pulmonary Hypertension Thoraxclinic, University Hospital Heidelberg, Heidelberg, Germany. 3 Department of Traslational Medical Sciences, “Federico II” Medicine School, Naples, Italy 4 Institute of Clinical Physiology, National Research Council, Pisa, Italy 5 Department of Cardiology, Second University of Naples - AORN dei Colli - Monaldi Hospital, Naples, Italy 6 Internal and Sub-intensive Medicine Department, A.O.U. "Ospedali Riuniti", Ancona, Italy 7 Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy 8 Department of Experimental Medicine, Sapienza University of Rome,Rome 9 Department of Cardiology, University Hospital "San Giovanni di Dio e Ruggi d'Aragona" 2
*these authors equally contributed to the work
Total word count: 3301 Corresponding author: Alberto Maria Marra, MD IRCCS SDN, Via Gianturco 113 80143 Naples, Italy Tel./Fax : +39 0818907452 Email: [email protected]
1
Graphical Abstract
Abstract
During the last 15 years, a real “paradigm-shift” occurred, due to the development of PAHtargeted drugs, leading to crucial improvements in symptoms, exercise capacity, hemodynamics and outcome of PAH patients. In order to describe differences regarding epidemiology and therapy in PAH according to gender, we performed a review of the available literature in “PubMed” and “Web of Science” databases. In order to find relevant articles, we combined each of the following the keywords “pulmonary arterial hypertension”, “gender”, “sex”, “men”, “woman”, “male”, “female”, “phosphodiesterase inhibitors”, “endothelin receptor antagonists”, “prostanoids”. While there is a substantial agreement among epidemiological studies in reporting an increased prevalence of pulmonary arterial hypertension (PAH) among women, male PAH patients are affected by a higher impairment of the right ventricular function and consequently experience poorer outcomes. With regards 2
to PAH-targeted drug administration, endothelin receptor antagonists (ERAs) and prostacyclin analogues (PC) show better treatment results in female PAH patients, while phosphodiesterase-5 inhibitors (PD5-I) seem to exert a more beneficial effect on male patients. However, to date no clear consensus could be formed by the available literature, which is constituted mainly by retrospective studies. Females with PAH are more prone to develop PAH, while males experience poorer outcomes. Females PAH might benefit more from ERAs and PC, while males seem to have more beneficial effects from PD5-I administration. However, more research is warranted in order to assess the most effective treatment for PAH patients according to gender.
Key words: Pulmonary arterial hypertension, gender, treatment, risk stratification, female, male
Introduction
Pulmonary hypertension (PH) is a clinical condition defined as a resting mean pulmonary arterial pressure (mPAP) ≥ 25 mmHg, invasively measured with right heart catheterization (RHC)1,2. Several conditions may cause PH such as chronic respiratory diseases, left heart failure and chronic thromboembolic disease3. Pulmonary arterial hypertension (PAH) is the best characterized form of PH and is defined hemodynamically by the presence of precapillary PH, with a pulmonary artery wedge pressure (PAWP) ≤ 15 mmHg and pulmonary vascular resistance (PVR) > 3 Wood units (WU) in the absence of other causes of precapillary PH such as PH due to lung diseases, CTEPH or other rare diseases2. The pathophysiological hallmark of PH is a progressive vascular remodeling with increased pulmonary vascular resistance and right ventricular overload that may ultimately lead to right 3
heart failure and death4. During the last 15 years, a real “paradigm-shift” occurred, due to the development of PAH-targeted drugs, leading to crucial improvements in symptoms, exercise capacity, hemodynamics and outcome of PAH patients5,6. However, most PH patients affected by the disease are still burdened by impaired exercise capacity7, skeletal and respiratory muscle function8, quality of life (QoL), right heart function and decreased survival9. In this scenario, several issues are still outstanding, like the so-called “estrogenparadox”10: although there is a pronounced tendency for the disease to develop in women, female PAH patients display better survival rates than males11–13. This review will focus on the gender-related epidemiological and pathophysiological differences in PAH and the possible implications for pharmacological treatment. A review of the available literature until the end of June 2016 was performed in “PubMed” and “Web of Science” databases by two independent investigators (A.M.M and A.S.). In order to find relevant articles, we combined each of the following the keywords “pulmonary arterial hypertension”, “gender”, “sex”, “men”, “woman”,
“male”,
“female”,
“phosphodiesterase
inhibitors”,
“endothelin
receptor
antagonists”, “prostanoids”.
Epidemiology In order to understand PAH features in male and female patients, important insights might be gathered from the several PAH-registries implemented in the last two decades. Table 1 displays the female/male ratio reported in the major PAH registries published over the last 3 decades. Even though these studies substantially differ in several aspects such as number of patients, number of involved centers, design, and country, all of them consistently report an increased prevalence of PAH in women, as shown by the female to male ratio, ranging from 1.7 to 4.1. However, according to the comparative, prospective registry of newly initiated therapies for pulmonary hypertension (COMPERA) registry, the female-male ratio in the elderly (> 65 y.o.) were significantly reduced (1.2:1.0)14. According 4
to the US-PHC registry, there is no difference with regards to PAH-etiology between males and females, except PAH due to anorexic-drug use which occurs exclusively in women (100%) and PAH associated with human immunodeficiency virus (HIV-APAH) which is more prevalent in male patients (87%)15. Accordingly, the Spanish registry of Pulmonary Arterial Hypertension (REHAP) found that the prevalence of men with HIV-APAH (42%) was increased in comparison to men with Idiopathic PAH (IPAH) (27%, p< 0.05 vs IPAH group). Similarly, the prevalence of men with PAH associated with connective tissue diseases (CTDAPAH) (10%) was reduced in comparison to the male IPAH patient group (p< 0.05)11. Consistently, a Chinese registry reported the female prevalence in
connective tissue
diseases- associated PAH (CTD-APAH) (85.4%) to be higher than the female prevalence in IPAH (69.9%, p=0.04)12. With regards to PAH severity, women seem to be affected by a more severe disease as shown by the higher female to male ratio in the group of patients with a WHO functional class (FC) III and IV (4.6:1.0 and 4.2:1.0, respectively) compared to patients with WHO FC I and II (2.9:1.0 and 3.4:1.0 ,respectively)16. With regards to clinical outcomes, female sex seems to be an independent protective factor (HR 0.78, CI: 0.4-1.5, p: 0.38) for death due to PAH, as reported by the Chinese registry12, whereas male sex is an independent predictor of death in the general PAH population (HR: 1.38, CI: 1.03-1.83, p:0.03). The risk of death is even higher in the IPAH subgroup (HR: 2.25, CI:1.31-3.72, p:0.002), according to REHAP registry11. Consistently, the French registry reported higher survival rates of female PAH (71.88%) than male PAH (60.69%) patients after 36 months of follow-up13. With regards to PAH outcomes the Chinese registry reported higher 1-year (93.5%) and 3-year (77.5%) survival rates of males with IPAH, than 1-year (71.1) and 3year (47.4%) survival rates of males affected by CTD-APAH (all p< 0.01)12. Such differences were not found in the same study with regards to female PAH patients12. Taken together the epidemiological data raised from registries of PAH patients depict a scenario where PAH is more prevalent in women. Typically, men are affected more by HIV-APAH and less by 5
CTD-APAH and IPAH than females. Despite women seem to have a more severe disease with higher hospitalization rates, male PAH patients show worse right ventricular (RV) function and lower RV improvement after initiating PAH targeted drugs. As a probable consequence of this difference in RV function, men are affected by a poorer outcome.
Pathophysiological background for gender-related differences in PAH: an issue remaining to be resolved.
The crucial role played by sexual steroids on the cardiovascular system has already been investigated in several studies18–21. The actual knowledge about the complexity of the interplay among sex hormones (estrogens, testosterone, and dehydroepiandrosterone sulfate) in the pulmonary circulation and right ventricle, may however only partially explain the so-called “PAH-female paradox”22. Several issues still remain to be solved. First, there are contradictory reports about estrogen and metabolites. In some studies, estrogens seem to exert protective effects in animal models of PAH23–25 while other studies linked estrogens and their metabolites to PAH development26–28. On the other hand, testosterone-induced vasodilatation in isolated human and rat pulmonary arteries was already demonstrated in several studies29–31 and therefore might have the potential to improve hemodynamics in patients with PH. However, this is in contrast with other animal studies which showed that ovariectomized female rats presented with a more severe disease compared with those who retained their ovaries25. A recent study performed by Ventetuolo and coworkers32 reported that genetic variations in estrogen metabolism and androgen signaling are associated with right ventricular morphology in a sex-specific manner. In this study, single nucleotide polymorphisms (SNP) of an enzyme implicated in estrogen metabolism (CYP1B1) was in tight linkage disequilibrium with SNPs associated with pulmonary hypertension, suggesting these pathways may underpin sexual dimorphism in RV failure and consequently in different 6
outcomes experienced by male and female PAH. In this regard, a decreased expression of CYP1B1 was already found in patients with heritable PAH (HPAH), while on the other hand a common polymorphism in the CYP1B1 gene was suggested to be associated with familial PAH risk26. In the same study mutations for the gene of bone morphogenetic protein receptor type 2 (BMPR2), in patients that phenotypically expressed familial PAH, have a lower urinary 2-hydroxyoestrogen/16α-hydroxyestrone ratio than unaffected mutation carriers (p = 0.006), which ultimately means that estrogens´ metabolism plays a role in the development of PAH26. Recently, an increased CYP1B1 expression was found in the pulmonary artery in patients with IPAH28. In the same study, a genetic knockout or pharmacological inhibition of CYP1B1 resulted in a protective role against the development of PAH in mouse models28. Taken together this evidence suggests that differences in the estrogen metabolism such as the expression of CYP1B1 rather than estrogens themselves may play a crucial role in the different disease prevalence and progression of PAH in women. Not only sexual steroid hormones seem to be involved in the pathophysiology of the disease. A deletion of signal transducer and activator of transcription 5a/b (STAT5a/b) in vascular smooth muscle cells was performed in hypoxic mice by Yang et al.33. Interestingly, this animal model is of particular interest because male mice exposed to chronic hypoxia develop PH more frequently than female animals26. In this study, the deletions of STAT5a/b in hypoxic females showed the severest manifestations of PH33. Furthermore, it was reported in the same study that late-stage plexiform lesions in patients of both sexes with IPAH and
HPAH showed reduced STAT5a/b33. The same authors hypothesized that
species-specific male ("pulsatile") vs. female ("more continuous") temporal patterns of circulating growth hormone (GH) levels may lead to different patterned activation of STAT5a/b in peripheral tissues in both sexes33. The role played by GH has already been investigated extensively in chronic left heart failure34,35, where pilot studies have already demonstrated a possible beneficial effect of GH replacement therapy36–38. 7
On the clinical side, this scenario is even more complicated. Epidemiological studies show that women are more prone to develop PAH (Table 1), whereas female PAH patients have better right ventricular function than their male counterparts39,40 and consequently better survival rates, taking into account that RV function is a major determinant of prognosis and functional capacity in PAH41–43. Specifically, a statistically significant difference between male and female PAH patients with regards to right ventricular (RV) ejection fraction (EF) was found39. Furthermore, females experienced a better improvement of RV EF after 1 year of PAH targeted therapy40. Moreover, in the same cohort, 39.0% of the difference in transplant-free survival between men and women was mediated through changes in RVEF after initiating PAH medical therapies40. Female PAH patients display also better pulmonary hemodynamics, as shown by a pooled analysis of 1211 subjects with IPAH from 11 randomized trials, in which was found that males with PAH show higher right atrial pressure (+1.36 mmHg, 95% CI 0.44-2.27, p=0.004), higher mean pulmonary arterial pressure (+5.43 mmHg, 95% CI 2.20-8.66, p= 0.001), lower cardiac index (-0.14 l · min -1· m-2, 95% CI -0.23-0.04, p=0.01) and higher pulmonary vascular resistance (+1.23 Woods Units, 95% CI 0.18-2.27, p=0.02) than females44. This differences in male patients were sufficient to translate into a 5-8% difference in mortality45. In conclusion, as suggested by a recent editorial published by Lahm46, currently available data cannot elucidate which are the net effects of sexual steroids on PAH and which interplay occurs between gender and PAH clinical features. In this regard, more research is warranted in order to elucidate the underpinnings of sex-related differences in PAH.
Gender related differences in PAH treatment Since the approval of the first PAH-targeted drug (epoprostenol)47 in 1999, a total amount of twelve new compounds has been subsequently approved for PAH management. This has 8
completely changed the clinical management of this disease, mainly because of the crucial improvements in symptoms, exercise capacity, hemodynamics, and outcome of PAH patients1. The available PAH-targeted drugs can be divided into three categories according to their specific mechanisms of action: endothelin receptors antagonists (ERA), drugs acting on the NO pathway (phosphodiesterase-5 inhibitors and guanylate cyclase stimulators), drugs acting on the prostacyclin (PC) pathway (prostacyclin analogues and IP receptor agonist). In the following paragraphs, the existing evidence of pharmacological activity and clinical effects of the aforementioned 3 groups with regards to any possible gender-related difference are summarized.
Endothelin receptor antagonists The key role played by endothelin-1 (ET-1) in the pathobiology of PAH is well characterized48,49. ET-1 exerts vasoconstrictor and mitogen effects through 2 distinct receptors which in turn are expressed in the pulmonary vascular smooth muscle cells, specifically endothelin A (ET-A) and B (ET-B) receptors50. ET-B receptors are expressed in endothelial cells, and their activation leads to release of vasodilators and anti-proliferative mediators such as nitric oxide (NO) and prostacylin (PC) which in turn may counterbalance the vasoconstrictive effects of ET-150. There are biological differences in the ET-1 production and effects. Men displayed higher ET-1 levels than women51,52. Stauffer et al. demonstrated in middle-aged and older healthy adults that men have a higher vasodilation than women under selective ET-A receptor inhibitions (24±5 % vs 9±5%, p<0.05), while women exhibit higher vasodilation than men with the dual ET-A and ET-B receptor blockade53. Up to date, 3 endothelin receptor antagonists (ERAs) have been approved for the treatment of PAH: bosentan, ambrisentan, and macitentan1. So far no pharmacokinetic and pharmacodynamics differences related to sex were recorded in clinical studies employing ERAs in PAH54. In this regard, a recently published Japanese 9
study showed no relevant clinical differences in macitentan pharmacokinetics in men and women, leading to the recommendation that no dose adjustment according to sex is needed55. A pooled analysis of six randomized clinical trials (Ambrisentan in Pulmonary Arterial Hypertension,
Randomized,
Studies [ARIES]-1; ARIES-2;
Double-Blind,
Placebo-Controlled, Multicenter, Efficacy
Bosentan: Randomized Trial of Endothelin Receptor
Antagonist Therapy [BREATHE]-1; BREATHE-2; sitaxsentan To Relieve Impaired Exercise [STRIDE]-1; STRIDE-2; and STRIDE-4) including 1130 patients showed a 29.7 m greater placebo-adjusted response to ERAs of the six-minute walking distance (6MWD) in women than in men (p= 0.03)56. In contrast, male patients affected by congenital heart disease-associated PAH (CHD-APAH) seem to benefit more than women from bosentan administration (+ 33 m at the 6MWD, p< 0.01)57. With regards to clinical outcomes the aforementioned pooled analysis56 showed a reduced risk of clinical events (death, lung transplant, atrial septostomy, hospitalization due to worsening PAH, withdrawal for worsening right-sided heart failure, or addition of prostacyclin analogs or phosphodiesterase inhibitors for PAH) after adjusting for study and baseline walk distance due to ERAs in women (OR: 0.27; 95% CI, 0.15-0.55) but not in men (OR:1.28; 95% CI, 0.22-7.49). However, in the study with an endothelin receptor antagonist in pulmonary arterial hypertension to improve clinical outcome (SERAPHIN) employing macitentan, no differences in clinical events were recorded between males with PAH (45 events/109 patients in the macitentan arm vs. 35 events/65 patients in the placebo arm, p: ns) and females with PAH (146 events/383 patients in the macitentan arm vs 81 events/185 patients in the placebo arm, p= ns)58. With regards to serious adverse events (SAE), a recently published analysis including a total of 2370 PAH patients showed no differences in SAE related to gender during ERAs administration59. 10
Drugs acting on the NO pathway (phosphodiesterase-5 inhibitors and guanylate cyclase stimulators)
A consistent body of evidence suggests the pivotal role played in PAH pathogenesis and development by NO, which is involved in modulating vascular tone and remodeling in the pulmonary vasculature4. Important differences between males and females are present in the NO pathway. In a study performed by Chan and colleagues, NO-mediated vasodilatation in murine mesenteric arteries exhibited sex-specific responses to stimulation of the NOsoluble guanylate cyclase (sGC) pathway60. Specifically, these investigators found that in male mice, NO-mediated vasodilatation was solely through the NO-sGC—cyclic guanosine monophosphate (cGMP) pathway. However, in female mice, in addition to NO-mediated vasodilatation via the NO-sGC-cGMP pathway, an sGC independent pathway for NO activity exists60. On the other hand, total NO biosynthesis, assessed by urinary 15-N nitrate excretion, was significantly higher in women compared with men matched by various demographic and anthropometric characteristics61. Phosphodiesterase-5 inhibitors (PD5-i) are a class of drugs, currently recommended for PAH treatment1. They act enhancing NO signaling by impeding the catabolism of cGMP, whose downstream effects are vasodilation and inhibition of cell proliferation3. Up to date, two PDE5-i are approved for PAH treatment: sildenafil and tadalafil. The latter was tested in the pulmonary arterial hypertension and response to tadalafil (PHIRST)-I trial, a double-blind, placebo-controlled, 16-week study of 405 patients with PAH62. In the PHIRST-I trial improved exercise capacity and QoL measures and reduced clinical worsening were recorded only in the group using 40 mg of tadalafil, while the groups with 2.5 mg, 10 mg and 20 mg of tadalafil did not experience any significant improvement62. A recently published post-hoc analysis of the PHIRST trial reported that men demonstrated 11
significantly greater odds of achieving an increase >33 m in the 6MWD (OR, 1.79; 95% CI, 1.04-3.08; p: 0.04), a 5-unit increase in physical component summary score of the Medical Outcomes Study Short Form-36 (SF-36) (OR, 1.87; 95% CI, 1.76-3.26; p: 0.03), and a 5unit increase in the mental component summary score of the SF-36 (OR : 2.02 95% CI,1.163.52; p: 0.01) than women63. A similar post-hoc analysis was performed in the SUPER trial64. In the subgroup analysis of this trial the improvement of 6MWD (primary end-point of the study) was statistically significant for both sexes. However, the placebo corrected changes in 6MWD seemed to be to a greater extent in males (~90 m in the three sildenafil groups) than in females (~45 m)64. Taken together, it seems that men affected by PAH benefit more than women from PDE5-i administration. A possible theoretical explanation might be found in the aforementioned underlying differences in NO metabolism, with higher NO endogenous biosynthesis in women than in men61. Moreover, men may be more NO deficient, and consequently, their response to enhanced NO signaling from PDE5-i may be more robust than that seen in women63. To date, no study has systematically addressed whether this category of compounds grants a better effect on one gender rather than the other. Another molecule was successfully tested and successively approved for PAH treatment: the soluble guanylate cyclase stimulator (sGC) riociguat, which acts both in synergism with endogenous NO and also directly stimulating soluble guanylate cyclase independently of NO availability65. Riociguat was tested in Pulmonary Arterial hyperTENsion sGC-stimulator Trial (PATENT)-166, where it significantly improved exercise capacity, pulmonary hemodynamics, and serum NTproBNP concentrations. In a post-hoc analysis, riociguat was also able to reduce right heart size and improve RV systolic function67. In the PATENT-1 study, no differences were recorded with regards to least square-mean treatment difference in change in 6MWD (primary end-point of the study) in females (73 m, 95%CI 20-55) and males (31 m, 95% CI -3-65) treated with riociguat66. This is probably due to the similar 12
pharmacokinetic profile of this drugs in both sexes which does not require a dose adjustment according to gender68.
Prostacyclin pathway (Prostacyclin analogues and Prostacyclin IP-receptor agonists)
The prostacyclin pathway was one of the first to be studied in PAH. Indeed, epoprostenol (a prostacyclin analogue) was the first PAH-targeted drug approved47,69. Data from the registry to prospectively describe the use of prolonged room temperature stable-epoprostenol in patients with pulmonary arterial hypertension (PROSPECT) showed, that male PAH patients receiving epoprostenol were burdened by a lower time without hospitalization (estimate 38.3% 5.9% vs 54.6% 3.2%, for men and women respectively, p<0.15)70. In the same study also the 1-year survival rate in men was lower than in women (71.0% 5.2% vs 88.0% 2.1%; p< 0.001)70. To date, no available data elucidates any possible differences in both sexes with regards to the other approved prostacyclin analogues (iloprost, beraprost, and trepostinil). The clinical use of prostacyclin analogues is strongly limited by AEs related to the delivery system such as pump malfunction, local site infection, catheter obstruction and sepsis3. Selexipag is an oral selective IP prostacyclin-receptor agonist that is structurally distinct from prostacyclin71. It was successfully tested in a large (1156 patients) event-driven, phase 3, randomized, double-blind, placebo-controlled trial of prostacyclin (PGI2) receptor agonist In pulmonary arterial hypertension (GRIPHON)72. In this study, selexipag administration was associated with a reduced risk of the primary composite end point of death or a complication related to PAH73. In this study, no differences in the primary end-point between men (48 events/116 patients in placebo arm vs 31 events/113 patients in selexipag arm, p= ns) and women (144 events / 466 patients in placebo arm vs 124 events /457 patients) occurred. 13
Table 2 shows a summary of the available differences regarding PAH in male and female patients.
Conclusions Women seem to be more affected by PAH, especially by IPAH and CTD-APAH, whereas men are more affected by HIV-APAH. Despite female patients with PAH have a higher WHO functional class, male PAH patients have a more impaired RV function and hemodynamics compared with females with PAH. For this reason, men affected by PAH have poorer outcomes than females. Regarding pharmacological data, post-hoc analyses of randomized controlled trials reveal that women with PAH seem to benefit more from ERAs and prostacyclin analogue administration, whereas PDE5-I administration seems to be preferable in males.
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24
Tables Table 1 Female/male ratio in principal PAH registries
Registry US-NIH74 US-PHC15 SMR75 Chinese12 REVEAL16 REHAP11 UK and Ireland76 FPHN (ItinerAIR) 13 COMPERA77
Cohort IPAH Group I PAH IPAH, CTD-APAH IPAH, HPAH Group I PAH Group I PAH,CTEPH IPAH, HPAH, Ax-PAH Group I PAH Group I PAH,CTEPH
Country USA USA UK (Scotland) China USA Spain UK, Ireland France G, B, N, I, A, S, UK
Design P R+P R P P R+P P P P
Centers 32 3 NA 1 55 31 8 17 28
Patiens 187 578 374 72 3515 1028 482 674 1283
F/M Ratio 1.7 3.3 2.3 2.4 3.8-4.1 2.4 1.4 1.9 1.8
Table 1 legend F: female, M: male, P: prospective, R: retrospective, PAH: pulmonary arterial hypertension IPAH: idiopathic PAH, CTD-PAH: connective tissue disease associated PAH, HPAH: heritable PAH, Ax-PAH: PAH associated with anorexic-drugs use, US-NIH: United States National Institute of Health, US-PHC: United States Pulmonary Hypertension Connection, SMR: Scottish Morbidity Record, REVEAL: Registry to Evaluate Early and Long-term PAH Disease Management, REHAP: Spanish registry of Pulmonary Arterial Hypertension, FPHN: French pulmonary hypertension network, COMPERA: Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension. USA: United States of America, UK: United Kingdom, G: Germany, B: Belgium, N: Netherlands, I: Italy, A: Austria, S: Switzerland.
25
Table 2 Gender related differences in prevalence, clinical function and treatment response Male Prevalence
Clinical function
Treatment response
general IPAH CTD-APAH HIV-APAH WHO functional class RV function hemodynamics Outcome
Female Higher Higher Higher
Higher
11–13,15,16,74–77 11 11 15
Better
16
Better Better poorer
reference
39,40 44 11–13
ERAs* Better 56 PDE5-i Better 63 prostanoids Better 70 *Men with CHD-APAH benefit more from ERAs than women 57
Table 2 legend IPAH: Idiopathic Pulmonary Arterial Hypertension; CTD-APAH: connective tissue disease associated Pulmonary Arterial Hypertension; HIV-APAH: HIV infection associated pulmonary arterial Hypertension; WHO: world health organization; RV: Right Ventricular; ERAs: endothelin receptor antagonists; PDE5-i: phosphodiesterase-5 inhibitors; CHDAPAH: congenital heart diseases associated pulmonary arterial hypertension.
26
S1043-6618(16)30780-0 http://dx.doi.org/doi:10.1016/j.phrs.2016.10.018 YPHRS 3370
To appear in:
Pharmacological Research
Received date: Revised date: Accepted date:
10-8-2016 30-9-2016 18-10-2016
Please cite this article as: Marra Alberto M, Benjamin Nicola, Eichstaedt Christina, Salzano Andrea, Arcopinto Michele, Gargani Luna, D´eAlto Michele, Argiento Paola, Falsetti Lorenzo, Giosia Paolo Di, Isidori Andrea M, Ferrara Francesco, Bossone Eduardo, Cittadini Antonio, Grunig ¨ Ekkehard.Gender-related Differences in Pulmonary Arterial Hypertension Targeted Drugs Administration.Pharmacological Research http://dx.doi.org/10.1016/j.phrs.2016.10.018 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Gender-related Differences in Pulmonary Arterial Hypertension Targeted Drugs Administration
Alberto M. Marra1*, MD; Nicola Benjamin2*, MSc; Christina Eichstaedt2*, PhD; Andrea Salzano3, MD; Michele Arcopinto3, MD; Luna Gargani4, MD, PhD; Michele D´Alto5, MD; Paola Argiento5, MD, PhD; Lorenzo Falsetti6, MD; Paolo Di Giosia7, MD; Andrea M. Isidori8, MD, PhD; Francesco Ferrara9, MD,PhD; Eduardo Bossone9, MD, PhD; Antonio Cittadini3, MD; Ekkehard Grünig2, MD
1
IRCCS SDN, Via Gianturco 113, 80143 Naples, Italy Centre for Pulmonary Hypertension Thoraxclinic, University Hospital Heidelberg, Heidelberg, Germany. 3 Department of Traslational Medical Sciences, “Federico II” Medicine School, Naples, Italy 4 Institute of Clinical Physiology, National Research Council, Pisa, Italy 5 Department of Cardiology, Second University of Naples - AORN dei Colli - Monaldi Hospital, Naples, Italy 6 Internal and Sub-intensive Medicine Department, A.O.U. "Ospedali Riuniti", Ancona, Italy 7 Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy 8 Department of Experimental Medicine, Sapienza University of Rome,Rome 9 Department of Cardiology, University Hospital "San Giovanni di Dio e Ruggi d'Aragona" 2
*these authors equally contributed to the work
Total word count: 3301 Corresponding author: Alberto Maria Marra, MD IRCCS SDN, Via Gianturco 113 80143 Naples, Italy Tel./Fax : +39 0818907452 Email: [email protected]
1
Graphical Abstract
Abstract
During the last 15 years, a real “paradigm-shift” occurred, due to the development of PAHtargeted drugs, leading to crucial improvements in symptoms, exercise capacity, hemodynamics and outcome of PAH patients. In order to describe differences regarding epidemiology and therapy in PAH according to gender, we performed a review of the available literature in “PubMed” and “Web of Science” databases. In order to find relevant articles, we combined each of the following the keywords “pulmonary arterial hypertension”, “gender”, “sex”, “men”, “woman”, “male”, “female”, “phosphodiesterase inhibitors”, “endothelin receptor antagonists”, “prostanoids”. While there is a substantial agreement among epidemiological studies in reporting an increased prevalence of pulmonary arterial hypertension (PAH) among women, male PAH patients are affected by a higher impairment of the right ventricular function and consequently experience poorer outcomes. With regards 2
to PAH-targeted drug administration, endothelin receptor antagonists (ERAs) and prostacyclin analogues (PC) show better treatment results in female PAH patients, while phosphodiesterase-5 inhibitors (PD5-I) seem to exert a more beneficial effect on male patients. However, to date no clear consensus could be formed by the available literature, which is constituted mainly by retrospective studies. Females with PAH are more prone to develop PAH, while males experience poorer outcomes. Females PAH might benefit more from ERAs and PC, while males seem to have more beneficial effects from PD5-I administration. However, more research is warranted in order to assess the most effective treatment for PAH patients according to gender.
Key words: Pulmonary arterial hypertension, gender, treatment, risk stratification, female, male
Introduction
Pulmonary hypertension (PH) is a clinical condition defined as a resting mean pulmonary arterial pressure (mPAP) ≥ 25 mmHg, invasively measured with right heart catheterization (RHC)1,2. Several conditions may cause PH such as chronic respiratory diseases, left heart failure and chronic thromboembolic disease3. Pulmonary arterial hypertension (PAH) is the best characterized form of PH and is defined hemodynamically by the presence of precapillary PH, with a pulmonary artery wedge pressure (PAWP) ≤ 15 mmHg and pulmonary vascular resistance (PVR) > 3 Wood units (WU) in the absence of other causes of precapillary PH such as PH due to lung diseases, CTEPH or other rare diseases2. The pathophysiological hallmark of PH is a progressive vascular remodeling with increased pulmonary vascular resistance and right ventricular overload that may ultimately lead to right 3
heart failure and death4. During the last 15 years, a real “paradigm-shift” occurred, due to the development of PAH-targeted drugs, leading to crucial improvements in symptoms, exercise capacity, hemodynamics and outcome of PAH patients5,6. However, most PH patients affected by the disease are still burdened by impaired exercise capacity7, skeletal and respiratory muscle function8, quality of life (QoL), right heart function and decreased survival9. In this scenario, several issues are still outstanding, like the so-called “estrogenparadox”10: although there is a pronounced tendency for the disease to develop in women, female PAH patients display better survival rates than males11–13. This review will focus on the gender-related epidemiological and pathophysiological differences in PAH and the possible implications for pharmacological treatment. A review of the available literature until the end of June 2016 was performed in “PubMed” and “Web of Science” databases by two independent investigators (A.M.M and A.S.). In order to find relevant articles, we combined each of the following the keywords “pulmonary arterial hypertension”, “gender”, “sex”, “men”, “woman”,
“male”,
“female”,
“phosphodiesterase
inhibitors”,
“endothelin
receptor
antagonists”, “prostanoids”.
Epidemiology In order to understand PAH features in male and female patients, important insights might be gathered from the several PAH-registries implemented in the last two decades. Table 1 displays the female/male ratio reported in the major PAH registries published over the last 3 decades. Even though these studies substantially differ in several aspects such as number of patients, number of involved centers, design, and country, all of them consistently report an increased prevalence of PAH in women, as shown by the female to male ratio, ranging from 1.7 to 4.1. However, according to the comparative, prospective registry of newly initiated therapies for pulmonary hypertension (COMPERA) registry, the female-male ratio in the elderly (> 65 y.o.) were significantly reduced (1.2:1.0)14. According 4
to the US-PHC registry, there is no difference with regards to PAH-etiology between males and females, except PAH due to anorexic-drug use which occurs exclusively in women (100%) and PAH associated with human immunodeficiency virus (HIV-APAH) which is more prevalent in male patients (87%)15. Accordingly, the Spanish registry of Pulmonary Arterial Hypertension (REHAP) found that the prevalence of men with HIV-APAH (42%) was increased in comparison to men with Idiopathic PAH (IPAH) (27%, p< 0.05 vs IPAH group). Similarly, the prevalence of men with PAH associated with connective tissue diseases (CTDAPAH) (10%) was reduced in comparison to the male IPAH patient group (p< 0.05)11. Consistently, a Chinese registry reported the female prevalence in
connective tissue
diseases- associated PAH (CTD-APAH) (85.4%) to be higher than the female prevalence in IPAH (69.9%, p=0.04)12. With regards to PAH severity, women seem to be affected by a more severe disease as shown by the higher female to male ratio in the group of patients with a WHO functional class (FC) III and IV (4.6:1.0 and 4.2:1.0, respectively) compared to patients with WHO FC I and II (2.9:1.0 and 3.4:1.0 ,respectively)16. With regards to clinical outcomes, female sex seems to be an independent protective factor (HR 0.78, CI: 0.4-1.5, p: 0.38) for death due to PAH, as reported by the Chinese registry12, whereas male sex is an independent predictor of death in the general PAH population (HR: 1.38, CI: 1.03-1.83, p:0.03). The risk of death is even higher in the IPAH subgroup (HR: 2.25, CI:1.31-3.72, p:0.002), according to REHAP registry11. Consistently, the French registry reported higher survival rates of female PAH (71.88%) than male PAH (60.69%) patients after 36 months of follow-up13. With regards to PAH outcomes the Chinese registry reported higher 1-year (93.5%) and 3-year (77.5%) survival rates of males with IPAH, than 1-year (71.1) and 3year (47.4%) survival rates of males affected by CTD-APAH (all p< 0.01)12. Such differences were not found in the same study with regards to female PAH patients12. Taken together the epidemiological data raised from registries of PAH patients depict a scenario where PAH is more prevalent in women. Typically, men are affected more by HIV-APAH and less by 5
CTD-APAH and IPAH than females. Despite women seem to have a more severe disease with higher hospitalization rates, male PAH patients show worse right ventricular (RV) function and lower RV improvement after initiating PAH targeted drugs. As a probable consequence of this difference in RV function, men are affected by a poorer outcome.
Pathophysiological background for gender-related differences in PAH: an issue remaining to be resolved.
The crucial role played by sexual steroids on the cardiovascular system has already been investigated in several studies18–21. The actual knowledge about the complexity of the interplay among sex hormones (estrogens, testosterone, and dehydroepiandrosterone sulfate) in the pulmonary circulation and right ventricle, may however only partially explain the so-called “PAH-female paradox”22. Several issues still remain to be solved. First, there are contradictory reports about estrogen and metabolites. In some studies, estrogens seem to exert protective effects in animal models of PAH23–25 while other studies linked estrogens and their metabolites to PAH development26–28. On the other hand, testosterone-induced vasodilatation in isolated human and rat pulmonary arteries was already demonstrated in several studies29–31 and therefore might have the potential to improve hemodynamics in patients with PH. However, this is in contrast with other animal studies which showed that ovariectomized female rats presented with a more severe disease compared with those who retained their ovaries25. A recent study performed by Ventetuolo and coworkers32 reported that genetic variations in estrogen metabolism and androgen signaling are associated with right ventricular morphology in a sex-specific manner. In this study, single nucleotide polymorphisms (SNP) of an enzyme implicated in estrogen metabolism (CYP1B1) was in tight linkage disequilibrium with SNPs associated with pulmonary hypertension, suggesting these pathways may underpin sexual dimorphism in RV failure and consequently in different 6
outcomes experienced by male and female PAH. In this regard, a decreased expression of CYP1B1 was already found in patients with heritable PAH (HPAH), while on the other hand a common polymorphism in the CYP1B1 gene was suggested to be associated with familial PAH risk26. In the same study mutations for the gene of bone morphogenetic protein receptor type 2 (BMPR2), in patients that phenotypically expressed familial PAH, have a lower urinary 2-hydroxyoestrogen/16α-hydroxyestrone ratio than unaffected mutation carriers (p = 0.006), which ultimately means that estrogens´ metabolism plays a role in the development of PAH26. Recently, an increased CYP1B1 expression was found in the pulmonary artery in patients with IPAH28. In the same study, a genetic knockout or pharmacological inhibition of CYP1B1 resulted in a protective role against the development of PAH in mouse models28. Taken together this evidence suggests that differences in the estrogen metabolism such as the expression of CYP1B1 rather than estrogens themselves may play a crucial role in the different disease prevalence and progression of PAH in women. Not only sexual steroid hormones seem to be involved in the pathophysiology of the disease. A deletion of signal transducer and activator of transcription 5a/b (STAT5a/b) in vascular smooth muscle cells was performed in hypoxic mice by Yang et al.33. Interestingly, this animal model is of particular interest because male mice exposed to chronic hypoxia develop PH more frequently than female animals26. In this study, the deletions of STAT5a/b in hypoxic females showed the severest manifestations of PH33. Furthermore, it was reported in the same study that late-stage plexiform lesions in patients of both sexes with IPAH and
HPAH showed reduced STAT5a/b33. The same authors hypothesized that
species-specific male ("pulsatile") vs. female ("more continuous") temporal patterns of circulating growth hormone (GH) levels may lead to different patterned activation of STAT5a/b in peripheral tissues in both sexes33. The role played by GH has already been investigated extensively in chronic left heart failure34,35, where pilot studies have already demonstrated a possible beneficial effect of GH replacement therapy36–38. 7
On the clinical side, this scenario is even more complicated. Epidemiological studies show that women are more prone to develop PAH (Table 1), whereas female PAH patients have better right ventricular function than their male counterparts39,40 and consequently better survival rates, taking into account that RV function is a major determinant of prognosis and functional capacity in PAH41–43. Specifically, a statistically significant difference between male and female PAH patients with regards to right ventricular (RV) ejection fraction (EF) was found39. Furthermore, females experienced a better improvement of RV EF after 1 year of PAH targeted therapy40. Moreover, in the same cohort, 39.0% of the difference in transplant-free survival between men and women was mediated through changes in RVEF after initiating PAH medical therapies40. Female PAH patients display also better pulmonary hemodynamics, as shown by a pooled analysis of 1211 subjects with IPAH from 11 randomized trials, in which was found that males with PAH show higher right atrial pressure (+1.36 mmHg, 95% CI 0.44-2.27, p=0.004), higher mean pulmonary arterial pressure (+5.43 mmHg, 95% CI 2.20-8.66, p= 0.001), lower cardiac index (-0.14 l · min -1· m-2, 95% CI -0.23-0.04, p=0.01) and higher pulmonary vascular resistance (+1.23 Woods Units, 95% CI 0.18-2.27, p=0.02) than females44. This differences in male patients were sufficient to translate into a 5-8% difference in mortality45. In conclusion, as suggested by a recent editorial published by Lahm46, currently available data cannot elucidate which are the net effects of sexual steroids on PAH and which interplay occurs between gender and PAH clinical features. In this regard, more research is warranted in order to elucidate the underpinnings of sex-related differences in PAH.
Gender related differences in PAH treatment Since the approval of the first PAH-targeted drug (epoprostenol)47 in 1999, a total amount of twelve new compounds has been subsequently approved for PAH management. This has 8
completely changed the clinical management of this disease, mainly because of the crucial improvements in symptoms, exercise capacity, hemodynamics, and outcome of PAH patients1. The available PAH-targeted drugs can be divided into three categories according to their specific mechanisms of action: endothelin receptors antagonists (ERA), drugs acting on the NO pathway (phosphodiesterase-5 inhibitors and guanylate cyclase stimulators), drugs acting on the prostacyclin (PC) pathway (prostacyclin analogues and IP receptor agonist). In the following paragraphs, the existing evidence of pharmacological activity and clinical effects of the aforementioned 3 groups with regards to any possible gender-related difference are summarized.
Endothelin receptor antagonists The key role played by endothelin-1 (ET-1) in the pathobiology of PAH is well characterized48,49. ET-1 exerts vasoconstrictor and mitogen effects through 2 distinct receptors which in turn are expressed in the pulmonary vascular smooth muscle cells, specifically endothelin A (ET-A) and B (ET-B) receptors50. ET-B receptors are expressed in endothelial cells, and their activation leads to release of vasodilators and anti-proliferative mediators such as nitric oxide (NO) and prostacylin (PC) which in turn may counterbalance the vasoconstrictive effects of ET-150. There are biological differences in the ET-1 production and effects. Men displayed higher ET-1 levels than women51,52. Stauffer et al. demonstrated in middle-aged and older healthy adults that men have a higher vasodilation than women under selective ET-A receptor inhibitions (24±5 % vs 9±5%, p<0.05), while women exhibit higher vasodilation than men with the dual ET-A and ET-B receptor blockade53. Up to date, 3 endothelin receptor antagonists (ERAs) have been approved for the treatment of PAH: bosentan, ambrisentan, and macitentan1. So far no pharmacokinetic and pharmacodynamics differences related to sex were recorded in clinical studies employing ERAs in PAH54. In this regard, a recently published Japanese 9
study showed no relevant clinical differences in macitentan pharmacokinetics in men and women, leading to the recommendation that no dose adjustment according to sex is needed55. A pooled analysis of six randomized clinical trials (Ambrisentan in Pulmonary Arterial Hypertension,
Randomized,
Studies [ARIES]-1; ARIES-2;
Double-Blind,
Placebo-Controlled, Multicenter, Efficacy
Bosentan: Randomized Trial of Endothelin Receptor
Antagonist Therapy [BREATHE]-1; BREATHE-2; sitaxsentan To Relieve Impaired Exercise [STRIDE]-1; STRIDE-2; and STRIDE-4) including 1130 patients showed a 29.7 m greater placebo-adjusted response to ERAs of the six-minute walking distance (6MWD) in women than in men (p= 0.03)56. In contrast, male patients affected by congenital heart disease-associated PAH (CHD-APAH) seem to benefit more than women from bosentan administration (+ 33 m at the 6MWD, p< 0.01)57. With regards to clinical outcomes the aforementioned pooled analysis56 showed a reduced risk of clinical events (death, lung transplant, atrial septostomy, hospitalization due to worsening PAH, withdrawal for worsening right-sided heart failure, or addition of prostacyclin analogs or phosphodiesterase inhibitors for PAH) after adjusting for study and baseline walk distance due to ERAs in women (OR: 0.27; 95% CI, 0.15-0.55) but not in men (OR:1.28; 95% CI, 0.22-7.49). However, in the study with an endothelin receptor antagonist in pulmonary arterial hypertension to improve clinical outcome (SERAPHIN) employing macitentan, no differences in clinical events were recorded between males with PAH (45 events/109 patients in the macitentan arm vs. 35 events/65 patients in the placebo arm, p: ns) and females with PAH (146 events/383 patients in the macitentan arm vs 81 events/185 patients in the placebo arm, p= ns)58. With regards to serious adverse events (SAE), a recently published analysis including a total of 2370 PAH patients showed no differences in SAE related to gender during ERAs administration59. 10
Drugs acting on the NO pathway (phosphodiesterase-5 inhibitors and guanylate cyclase stimulators)
A consistent body of evidence suggests the pivotal role played in PAH pathogenesis and development by NO, which is involved in modulating vascular tone and remodeling in the pulmonary vasculature4. Important differences between males and females are present in the NO pathway. In a study performed by Chan and colleagues, NO-mediated vasodilatation in murine mesenteric arteries exhibited sex-specific responses to stimulation of the NOsoluble guanylate cyclase (sGC) pathway60. Specifically, these investigators found that in male mice, NO-mediated vasodilatation was solely through the NO-sGC—cyclic guanosine monophosphate (cGMP) pathway. However, in female mice, in addition to NO-mediated vasodilatation via the NO-sGC-cGMP pathway, an sGC independent pathway for NO activity exists60. On the other hand, total NO biosynthesis, assessed by urinary 15-N nitrate excretion, was significantly higher in women compared with men matched by various demographic and anthropometric characteristics61. Phosphodiesterase-5 inhibitors (PD5-i) are a class of drugs, currently recommended for PAH treatment1. They act enhancing NO signaling by impeding the catabolism of cGMP, whose downstream effects are vasodilation and inhibition of cell proliferation3. Up to date, two PDE5-i are approved for PAH treatment: sildenafil and tadalafil. The latter was tested in the pulmonary arterial hypertension and response to tadalafil (PHIRST)-I trial, a double-blind, placebo-controlled, 16-week study of 405 patients with PAH62. In the PHIRST-I trial improved exercise capacity and QoL measures and reduced clinical worsening were recorded only in the group using 40 mg of tadalafil, while the groups with 2.5 mg, 10 mg and 20 mg of tadalafil did not experience any significant improvement62. A recently published post-hoc analysis of the PHIRST trial reported that men demonstrated 11
significantly greater odds of achieving an increase >33 m in the 6MWD (OR, 1.79; 95% CI, 1.04-3.08; p: 0.04), a 5-unit increase in physical component summary score of the Medical Outcomes Study Short Form-36 (SF-36) (OR, 1.87; 95% CI, 1.76-3.26; p: 0.03), and a 5unit increase in the mental component summary score of the SF-36 (OR : 2.02 95% CI,1.163.52; p: 0.01) than women63. A similar post-hoc analysis was performed in the SUPER trial64. In the subgroup analysis of this trial the improvement of 6MWD (primary end-point of the study) was statistically significant for both sexes. However, the placebo corrected changes in 6MWD seemed to be to a greater extent in males (~90 m in the three sildenafil groups) than in females (~45 m)64. Taken together, it seems that men affected by PAH benefit more than women from PDE5-i administration. A possible theoretical explanation might be found in the aforementioned underlying differences in NO metabolism, with higher NO endogenous biosynthesis in women than in men61. Moreover, men may be more NO deficient, and consequently, their response to enhanced NO signaling from PDE5-i may be more robust than that seen in women63. To date, no study has systematically addressed whether this category of compounds grants a better effect on one gender rather than the other. Another molecule was successfully tested and successively approved for PAH treatment: the soluble guanylate cyclase stimulator (sGC) riociguat, which acts both in synergism with endogenous NO and also directly stimulating soluble guanylate cyclase independently of NO availability65. Riociguat was tested in Pulmonary Arterial hyperTENsion sGC-stimulator Trial (PATENT)-166, where it significantly improved exercise capacity, pulmonary hemodynamics, and serum NTproBNP concentrations. In a post-hoc analysis, riociguat was also able to reduce right heart size and improve RV systolic function67. In the PATENT-1 study, no differences were recorded with regards to least square-mean treatment difference in change in 6MWD (primary end-point of the study) in females (73 m, 95%CI 20-55) and males (31 m, 95% CI -3-65) treated with riociguat66. This is probably due to the similar 12
pharmacokinetic profile of this drugs in both sexes which does not require a dose adjustment according to gender68.
Prostacyclin pathway (Prostacyclin analogues and Prostacyclin IP-receptor agonists)
The prostacyclin pathway was one of the first to be studied in PAH. Indeed, epoprostenol (a prostacyclin analogue) was the first PAH-targeted drug approved47,69. Data from the registry to prospectively describe the use of prolonged room temperature stable-epoprostenol in patients with pulmonary arterial hypertension (PROSPECT) showed, that male PAH patients receiving epoprostenol were burdened by a lower time without hospitalization (estimate 38.3% 5.9% vs 54.6% 3.2%, for men and women respectively, p<0.15)70. In the same study also the 1-year survival rate in men was lower than in women (71.0% 5.2% vs 88.0% 2.1%; p< 0.001)70. To date, no available data elucidates any possible differences in both sexes with regards to the other approved prostacyclin analogues (iloprost, beraprost, and trepostinil). The clinical use of prostacyclin analogues is strongly limited by AEs related to the delivery system such as pump malfunction, local site infection, catheter obstruction and sepsis3. Selexipag is an oral selective IP prostacyclin-receptor agonist that is structurally distinct from prostacyclin71. It was successfully tested in a large (1156 patients) event-driven, phase 3, randomized, double-blind, placebo-controlled trial of prostacyclin (PGI2) receptor agonist In pulmonary arterial hypertension (GRIPHON)72. In this study, selexipag administration was associated with a reduced risk of the primary composite end point of death or a complication related to PAH73. In this study, no differences in the primary end-point between men (48 events/116 patients in placebo arm vs 31 events/113 patients in selexipag arm, p= ns) and women (144 events / 466 patients in placebo arm vs 124 events /457 patients) occurred. 13
Table 2 shows a summary of the available differences regarding PAH in male and female patients.
Conclusions Women seem to be more affected by PAH, especially by IPAH and CTD-APAH, whereas men are more affected by HIV-APAH. Despite female patients with PAH have a higher WHO functional class, male PAH patients have a more impaired RV function and hemodynamics compared with females with PAH. For this reason, men affected by PAH have poorer outcomes than females. Regarding pharmacological data, post-hoc analyses of randomized controlled trials reveal that women with PAH seem to benefit more from ERAs and prostacyclin analogue administration, whereas PDE5-I administration seems to be preferable in males.
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Tables Table 1 Female/male ratio in principal PAH registries
Registry US-NIH74 US-PHC15 SMR75 Chinese12 REVEAL16 REHAP11 UK and Ireland76 FPHN (ItinerAIR) 13 COMPERA77
Cohort IPAH Group I PAH IPAH, CTD-APAH IPAH, HPAH Group I PAH Group I PAH,CTEPH IPAH, HPAH, Ax-PAH Group I PAH Group I PAH,CTEPH
Country USA USA UK (Scotland) China USA Spain UK, Ireland France G, B, N, I, A, S, UK
Design P R+P R P P R+P P P P
Centers 32 3 NA 1 55 31 8 17 28
Patiens 187 578 374 72 3515 1028 482 674 1283
F/M Ratio 1.7 3.3 2.3 2.4 3.8-4.1 2.4 1.4 1.9 1.8
Table 1 legend F: female, M: male, P: prospective, R: retrospective, PAH: pulmonary arterial hypertension IPAH: idiopathic PAH, CTD-PAH: connective tissue disease associated PAH, HPAH: heritable PAH, Ax-PAH: PAH associated with anorexic-drugs use, US-NIH: United States National Institute of Health, US-PHC: United States Pulmonary Hypertension Connection, SMR: Scottish Morbidity Record, REVEAL: Registry to Evaluate Early and Long-term PAH Disease Management, REHAP: Spanish registry of Pulmonary Arterial Hypertension, FPHN: French pulmonary hypertension network, COMPERA: Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension. USA: United States of America, UK: United Kingdom, G: Germany, B: Belgium, N: Netherlands, I: Italy, A: Austria, S: Switzerland.
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Table 2 Gender related differences in prevalence, clinical function and treatment response Male Prevalence
Clinical function
Treatment response
general IPAH CTD-APAH HIV-APAH WHO functional class RV function hemodynamics Outcome
Female Higher Higher Higher
Higher
11–13,15,16,74–77 11 11 15
Better
16
Better Better poorer
reference
39,40 44 11–13
ERAs* Better 56 PDE5-i Better 63 prostanoids Better 70 *Men with CHD-APAH benefit more from ERAs than women 57
Table 2 legend IPAH: Idiopathic Pulmonary Arterial Hypertension; CTD-APAH: connective tissue disease associated Pulmonary Arterial Hypertension; HIV-APAH: HIV infection associated pulmonary arterial Hypertension; WHO: world health organization; RV: Right Ventricular; ERAs: endothelin receptor antagonists; PDE5-i: phosphodiesterase-5 inhibitors; CHDAPAH: congenital heart diseases associated pulmonary arterial hypertension.
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